Regulation of Alzheimer’s disease amyloid- formation by casein kinase I

Alzheimer’s disease (AD) is associated with accumulation of the neurotoxic peptide amyloid(A ), which is produced by sequential cleavage of amyloid precursor protein (APP) by the aspartyl protease -secretase and the presenilin-dependent protease -secretase. An increase of casein kinase 1 (CK1) expression has been described in the human AD brain. We show, by using in silico analysis, that APP, -secretase, and -secretase subunits contain, in their intracellular regions, multiple CK1 consensus phosphorylation sites, many of which are conserved among human, rat, and mouse species. Overexpression of constitutively active CK1 , one of the CK1 isoforms expressed in brain, leads to an increase in A peptide production. Conversely, three structurally dissimilar CK1specific inhibitors significantly reduced endogenous A peptide production. By using mammalian cells expressing the C-terminal fragment of APP, it was possible to demonstrate that CK1 inhibitors act at the level of -secretase cleavage. Importantly, Notch cleavage was not affected. Our results indicate that CK1 represents a therapeutic target for prevention of A formation in AD.